PROJECT SUMMARY/ABSTRACT By discovering the strategies that animals normally use to renew and regenerate their tissues, we can lay a foundation for regenerative approaches in humans. One of the principal long-term goals of my laboratory is to understand mammalian renewal and regeneration by integrating developmental and evolutionary perspectives. To do this, we are using the dentition as a model and are taking advantage of a remarkable property that is found in diverse mammalian species, which is the ability to grow teeth continuously based on the presence of adult stem cells. Despite initial progress, many gaps and challenges in our knowledge remain. We are still in the early stages of understanding how dental stem cells in the incisor epithelium behave, and we know very little about the mesenchymal stem cells. We also have a great deal to learn about how dental stem cells evolved and how they arise in the embryo during development. The overall scope of the research program proposed here will be to contend with these fundamental questions: How do adult stem cells enable the organ to renew? How do the stem cells in teeth respond to environmental influences such as hibernation and force? How did stem cells emerge during evolution of the mammalian dentition? How do progenitor cells in the embryo provide the starting materials for tooth development? Can we target tooth progenitors to cure disease? The impact of our work will be to provide a solid basic science foundation for future regenerative approaches by obtaining deep insight into a system of natural mammalian dental renewal.